The present invention relates to methods of treatment of a diseased patient in which a dose of at least one heavy metal such as a noble metal, e.g. gold, is delivered to a patient.
In the present application the term “patient” covers all kinds of “mammals” defined as warm-blooded higher vertebrates that nourish their young with milk secreted by mammary glands. In particular, this definition includes humans and other animals that are capable of producing an immune response.
When used in the present application the term “heavy metal” refers to heavy metals as defined by the United Nations Economic Commission for Europe Heavy Metals Protocol: “ . . . those metals or, in some cases, metalloids which are stable and have a density greater than 4.5 g/cm3 and their compounds”. However, for use in the present application metalloids are not contemplated and therefore not included.
The term “reticulated heavy metal” is in the present invention used for a heavy metal surface delicately wrinkled.
Heavy metals such as the noble metals gold and silver, and mercury have been used since ancient times as cures for a wide range of diseases including tuberculosis, but only within the last 50 years, a more rational basis for the therapeutic use of gold and silver has emerged. The use of gold implants originates from acupuncture where gold needles seem to have been used quite often. In the early 1970s some US veterinarians started to treat dogs suffering from hip dysplasia with gold implants, and since then several veterinary surgeons and medical doctors have implemented the technique on their patients. The authorized and scientifically well-founded use of gold in rheumatoid arthritis is mainly performed with various gold-thio compounds such as gold sodium thiomalate, commercially available from Aventis Pharma as MYOCRISIN®.
Quite early on it was suggested that gold inhibits the lysosomal enzymes of phagocytotic cells in the inflamed synovial tissue. Although knowledge of the effect of gold ions on the cellular immune response is still relatively sparse, it is recognized that gold ions are powerful inhibitors of macrophages and polymorphonuclear leucocytes, and the ability of gold-thio compounds to suppress inflammation in rheumatic joints was established a long time ago. Gold ions are believed to inhibit antigen processing and to suppress NF-kappa B binding activity and 1-kappa B-kinase activation, resulting in a reduced production of proinflammatory cytokines.
Conventional gold therapy uses rather large doses i.e. the amount of released gold ions are high and involve the whole organism. As gold ions are toxic to the kidneys treatment with gold compounds take place only at hospitals. There are evidence suggesting that very low doses of gold can have pharmacological effects. [Gold And Its Relationship To Neurological/Glandular Conditions; Douglas G. Richards, Ph.D., David L. McMillin, M.A., Eric A. Mein, M.D., Carl D. Nelson, D.C., Intern. J. Neuroscience, 2002, Vol. 112, pages 31-53]. Gold drugs used in rheumatoid arthritis are typically administered in relatively large doses and the relationship between dosage and response is not simple. Dosages as low as 10 mg/week appear according to prior art to be no different from 50 mg/week, which in turn is as effective as 150 mg/week [Speight T M, Holford N H G, (editors). Avery's Drug treatment. 4th edition. Auckland: Adis; 1997: p. 1129].
Kidney damage after treatment with gold compounds is often a typical complication. No prior evidence exists of how little a dose of a gold compounds that can still produce a therapeutic effect. Nor does the prior art discloses unambiguously in which geometrical shape pure heavy metals, such as metallic gold, are optimum applied and delivered to a patient for treatment of diseases and maladies to achieve therapeutic effects.
U.S. Pat. No. 4,606,354 discloses an implant for treatment of arthritic related pain. A carbon fiber coated with a discontinuous gold plating constitutes a self-contained, body-demanded galvanic couples that uses the body joint fluids as an electrical conductive electrolyte. This implant delivers gold ions in a very confined area and the continuous effect relies entirely upon a postulated galvanic action between gold and carbon in combination with the presence of sufficient amounts of body fluids. Another implant for treating rheumatoid arthritis is known from U.S. Pat. No. 4,405,311. Electrically generated gold ions are injected in the patient's joint. This implant needs to be constantly powered by an external battery. Also, U.S. Pat. No. 3,877,461 describes a contraceptive vas deferens valve implant using a.o. a cobber coating as a spermicidal agent and a gold taping wire purely serving as an ingrowth means.
In the method according to WO 94/21288, a composition comprising a colloidal metal in combination with a substance which normally is toxic to a human and an animal capable of producing an immune response is administered to the human or animal. The colloidal metal is added solely to make the toxic substance less toxic or non-toxic to the recipient. WO 94/21288 is however silent about the use of delivering pure metallic gold to the patient. The colloidal metal suggested in WO 94/21288 is HAuCl4. However hydrogen tetrachloroaurate is not a colloidal metal as such but the chemical precursor in the general methods for producing colloidal gold, in which gold nanoparticles are produced in a liquid by reduction of HAuCl4.
Autometallographic (AMG) silver enhancement has been implemented as a tool for enhancing colloidal gold particles bound to antibodies and enzymes. [Danscher, G. (1981) Localization of gold in biological tissue. A photochemical method for light and electronmicroscopy. Histochemistry 71: 81-88; Danscher, G. and J. O. R. Nørgaard (1983) J. Histochem. Cytochem. 31/12: 1394-1398. Holgate et al. (1983) J. of Histochem. Cytochem. 31/7, 938-944]. As is clear from the above the prior art has recognized some advantages of gold treatments but still struggles with the problem of delivering a correct dose and form of heavy metals, in particular gold, to the patient in order to suppress the immuno reactive cells. To obtain suppression of the immuno reactive cells and at the same time avoid or minimize manifestation of undesirable effects it is essential that the correct dose of heavy metal is delivered in a manner and amount appropriate and sufficient for a diseased patient. The present invention now addresses the shortcomings of the prior art in a novel and unexpected way.